Metastasis leads to most cancer-related deaths, yet many of the molecular determinants and their mechanisms of action remain unknown. This proposal details a career development plan and research objectives to further the training of Dr. Monte Winslow during his studies on cancer metastasis. While supervised by Dr. Tyler Jacks during the mentored phase of the K99, program the applicant will devote his time to the major objective of transitioning his gene-discovery work into functional validation. The Jacks laboratory and the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology are the ideal environment in which to conduct these studies, as they will provide all equipment, facilities and intellectual stimulation required for success. The applicant's ultimate goal is to direct an academic research laboratory addressing questions regarding the biology and mechanistic details that control metastasis, with the hope that this knowledge may, in time, impact human health. The proposed research builds heavily on preliminary data that uncovered down-regulation of the homeobox transcription factor Nkx2-1 as an important regulator of lung tumor progression and metastasis. Interrogation of Nkx2-1 regulated genes and analysis of tumors at defined stages of development indicate that Nkx2-1 may constrain tumors by repressing embryonically-restricted transcriptional regulators and components of the extracellular matrix. The proposed experiments will address the role of these factors in regulating metastasis-associated phenotype in vitro and tumor progression and metastasis in an autochthonous lung adenocarcinoma model in vivo. These experiments will contribute to our understanding of the molecular underpinning of lung adenocarcinoma progression towards malignancy consistent with the mission of the National Cancer Institute. The Specific Aims of this proposal are to: (1) Determine the relevance of Nkx2-1 and Nkx2-1-regulated genes to lung adenocarcinoma progression;(2) Interrogate the function of candidate genes in an autochthonous lung adenocarcinoma mouse model;(3) Determine the effect of Hmga2 loss on tumor progression and metastasis. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer deaths worldwide, with a majority of the mortality associated with metastatic cancer that has spread to other organs. We have identified, and propose to further investigate, the role of several proteins that drive tumor progression and metastasis. My goals are to understand the molecular basis of metastasis and ultimately, to use this information to treat metastatic lesions and prevent metastatic spread.